The alcohol-related phenotypes that are commonly used in genetic studies are often based on broadly defined diagnostic criteria. We have focused our previous research on the development of intermediate phenotypes, or endophenotypes, that are more proximal to the biological mechanisms that underlie the etiology of alcohol dependence (e.g., acute effects of alcohol). The extant literature as well as our own previous studies clearly suggests that <opiate receptors and the <opiate receptor gene (OPRM1) are important in terms of the acute effects of alcohol. Likewise, our preliminary data indicate that cannabinoid (CB1) receptors and the cannabinoid receptor gene (CNR1) strongly influence affective responses to alcohol. The first aim of the proposed research is to replicate and extend our previous research by testing whether a functional SNP (A118G) in the OPRM1 influences the effects of an acute infusion of alcohol, as compared to a saline infusion, on physiological and subjective measures of stimulation, sedation, and mood. The first aim will also test whether this effect is specific to alcohol dependent individuals by comparing alcohol dependent individuals with healthy, non-dependent drinkers. The second aim will replicate and extend our research on the CNR1 by testing whether a functional SNP in the CNR1 influences acute responses to alcohol and whether this effect is more pronounced among alcohol dependent individuals. Finally, the third aim will examine the additive effects of these two SNPs. The proposed study is designed to both build on the strengths and address the limitations of our previous work by utilizing an alcohol infusion protocol (i.e., clamping protocol) to reduce unwanted pharmacokinetic and pharmacodynamic variability across individuals, thereby improving the overall power to detect the effects of the genetic variants and their interaction. In addition, the proposed research will address the limitations of our previous work by using a saline control condition and by testing both alcohol dependent and healthy non- dependent controls. These design improvements will allow us to examine whether or not the effect of genetic variants in the OPRM1 and CNR1 have an immediate effect on responses to alcohol or whether these variants interact with repeated exposure to alcohol to produce an enhanced sensitivity to the effects of alcohol (i.e., a gene by environment interaction) that is more evident in alcohol dependent individuals. Despite rapid advances in our understanding of the human genome, the identification of genetic factors that influence the etiology and treatment of alcohol dependence has yet to materialize. This research is designed to identify specific genetic variations that are related to how people respond to alcohol and identify how they are related to alcohol dependence. Improvements in our understanding of genetic factors and neurobiological mechanisms that influence the etiology of alcohol dependence is expected to have implications for new prevention and treatment approaches.